Heterocyclic carbamates, process for their preparation and medicaments

ABSTRACT

The invention relates to heterocyclic carbamates of the formula (I) ##STR1## processes for their preparation and medicaments containing them.

The invention relates to compounds of the general formula (I) ##STR2##in which a)

X denotes the group CR⁴ and Y denotes the group CR⁵ where

R¹ stands for a C₁ - to C₆ - lower alkyl radical, for a substituted C₁ -to C₆ - lower alkyl radical, for an aryl-C₁ - to C₆ - lower alkylradical, for an aryl radical or for a heterocyclic radical,

R² and R³ independently of one another stand for radicals of thefollowing meaning:

hydrogen atoms, C₁ - to C₆ - lower alkyl radicals, C₁ - to C₆ - loweralkoxy radicals, C₁ - to C₆ - lower alkylthio radicals, halogen atoms,nitro groups, hydroxyl groups, trifluoromethyl radicals, cyano radicals,sulpho radicals, C₁ - to C₆ - lower alkylsulphonyl groups, carboxylicacid groups, C₁ - to C₆ - lower alkoxycarbonyl radicals, C₁ - to C₆ -lower alkoxycarbonyloxy radicals, acetamido radicals, benzamido radicalsor the group --N(R⁶)R⁷,

R⁴ and R⁵ independently of one another stand for a hydrogen atom, for aC₁ - to C₆ - lower alkyl radical, for a substituted C₁ - to C₆ - loweralkyl radical, for an aryl-C₁ - to C₆ - lower alkyl radical or for anaryl radical,

m and n independently of one another are equal to 0, 1, 2, 3, or 4, and

R⁶ and R⁷ independently of one another stand for a hydrogen atom or aC₁ - to C₆ - lower alkyl radical,

or in which

b)

X and Y denote a nitrogen atom, where

R¹ stands for a methyl radical, for a C₃ - to C₆ - lower alkyl radical,for a substituted C₁ - to C₆ - lower alkyl radical, for an aryl-C₁ - toC₆ - lower alkyl radical, for an aryl radical or for a heterocyclicradical,

R² and R³ independently of one another stand for radicals of thefollowing meaning:

hydrogen atoms, C₁ - to C₆ - lower alkyl radicals, C₁ - to C₆ - loweralkoxy radicals, C₁ - to C₆ - lower alkylthio radicals, halogen atoms,nitro groups, hydroxyl groups, trifluoromethyl radicals, cyano radicals,sulpho radicals, C₁ - to C₆ - lower alkylsulphonyl groups, carboxylicacid groups, C₁ - to C₆ - lower alkoxycarbonyl radicals, C₁ - to C₆ -lower alkoxycarbonyloxy radicals, acetamido radicals, benzamido radicalsor the group --N(R⁶)R⁷, and

m and n, R⁶ and R⁷ have the meanings mentioned under a),

with the proviso that if R¹ denotes a methyl radical, an unsubstitutedC₃ - to C₆ - lower alkyl radical, a phenyl radical or a benzyl radical,at least one radical R² or R³ is different from a hydrogen atom or ahalogen atom,

or in which

c)

X denotes a nitrogen atom and Y denotes the group CR⁵, where

R¹ stands for a substituted C₁ - to C₆ - lower alkyl radical, for anaryl-C₁ - to C₆ - lower alkyl radical, for an aryl radical or for aheterocyclic radical,

R² and R³ independently of one another have the meanings mentioned undera),

R⁵ stands for a hydrogen atom or for a C₁ - to C₆ - lower alkyl radical,and

m and n, R⁶ and R⁷ have the meanings mentioned under a),

or in which

d)

X denotes a nitrogen atom and Y denotes the group CR⁵, where

R¹ stands for a C₁ - to C₆ - lower alkyl radical, for a substituted C₁ -to C₆ - lower alkyl radical, for an aryl-C₁ - to C₆ - lower alkylradical, for an aryl radical or for a heterocyclic radical,

R² and R³ independently of one another have the meanings mentioned undera),

R⁵ stands for a substituted C₁ - to C₆ - lower alkyl radical, foe anaryl-C₁ - to C₆ - lower alkyl radical or for an aryl radical, and

m and n, R⁶ and R⁷ have the meanings mentioned under a),

or in which

e)

Y denotes a nitrogen atom and X denotes the group CR⁴, where

R¹ stands for a C₁ - to C₆ - lower alkyl radical, for a substituted C₁ -to C₆ - lower alkyl radical, for an aryl-C₁ - to C₆ - lower alkylradical, for an aryl radical or for a heterocyclic radical,

R² and R³ independently of one another have the meanings mentioned undera),

R⁴ stands for a substituted C₁ - to C₆ - lower alkyl radical or for aradical of the general formula (II)

    --Z--R.sup.8                                               (II)

where Z stands for a carbonyl or carboxyl group, a sulphur atom or anoxygen atom and

R⁸ stands for a C₁ - to C₆ - lower alkyl radical, for a substituted C₁ -to C₆ - lower alkyl radical, for an aryl-C₁ - to C₆ - lower alkylradical or for an aryl radical, and

m and n, R⁶ and R⁷ have the meanings mentioned under a),

or in which

f)

Y denotes a nitrogen atom and X denotes the group CR⁴, where

R¹ stands for a substituted C₁ - to C₆ - lower alkyl radical, for anaryl radical or for a heterocyclic radical,

R² and R³ independently of one another have the meanings mentioned undera),

R⁴ stands for a hydrogen atom, for a C₁ - to C₆ - lower alkyl radical,for a substituted C₁ - to C₆ - lower alkyl radical, for an aryl-C₁ - toC₆ - lower alkyl radical or for an aryl radical, and

m and n, R⁶ and R⁷ have the meanings mentioned under a),

with the proviso that if R², R³ and R⁴ denote hydrogen atoms, R¹ isdifferent from an unsubstituted phenyl radical,

and

their salts with physiologically tolerable acids and bases.

Compounds of the general formula (I) are to be emphasized in which Xdenotes the group CR⁴ and Y denotes the group CR⁵ and R¹, R², R³, R⁴,R⁵, m and n have the meanings mentioned under Claim 1a.

Compounds of the general formula (I) are further to be emphasized inwhich X and Y denote a nitrogen atom and R¹, R², R³ m and n have themeanings mentioned under Claim 1b.

Compounds of the general formula (I) are further to be emphasized inwhich X denotes a nitrogen atom and Y denotes the group CR⁵ and R¹, R²,R³, R⁵, m and n have the meanings mentioned under Claim 1c.

Compounds of the general formula (I) are further to be emphasized inwhich X denotes a nitrogen atom and Y denotes the group CR⁵ and R¹, R²,R³, R⁵, m and n have the meanings mentioned under Claim 1d.

Compounds of the general formula (I) are further to be emphasized inwhich Y denotes a nitrogen atom and X denotes the group CR⁴ and R¹, R²,R³, R⁴, R⁸, m and n have the meanings mentioned under Claim 1e.

For the various substituents or radicals mentioned in connection withthe present application description the following explanations apply:

Examples of C₁ - to C₆ - lower alkyl radicals are unbranched andbranched hydrocarbon radicals having one to six carbon atoms such asmethyl radicals, ethyl radicals, n-propyl radicals, isopropyl radicals,n-butyl radicals, isobutyl radicals, 1-methylpropyl radicals, tert-butylradicals, n-pentyl radicals, 1-methylbutyl radicals, 2-methylbutylradicals, 3-methylbutyl radicals, 1,1-dimethylpropyl radicals,2,2-dimethylpropyl radicals, 1,2-dimethylpropyl radicals, 1-ethylpropylradicals, n-hexyl radicals, 1-methylpentyl radicals, 2-methylpentylradicals, 3-methylpentyl radicals, 4-methylpentyl radicals,1,1-dimethylbutyl radicals, 2,2-dimethylbutyl radicals,3,3-dimethylbutyl radicals, 1,2-dimethylbutyl radicals,2,3-dimethylbutyl radicals, 1,3-dimethylbutyl radicals, 1-ethylbutylradicals, 2-ethylbutyl radicals, 1,1,2-trimethylpropyl radicals,1,2,2-trimethylpropyl radicals, 1-ethyl-2-methylpropyl radicals or1-ethyl-1-methylpropyl radicals. Methyl radicals, ethyl radicals,n-propyl radicals, isopropyl radicals, n-butyl radicals or isobutylradicals are preferred here. Ethyl radicals, isopropyl radicals andisobutyl radicals are particularly preferred.

If in the present application the expression "lower alkyl" appears onits own or in combination with other functional groups (e.g. loweralkoxy, lower alkoxy-carbonyl, or lower alkylthio groups), thisexpression has the definitions indicated above.

Examples of substituted C₁ - to C₆ - lower alkyl radicals are theabovementioned lower alkyl radicals having one to six carbon atoms,which are substituted once or twice by identical or different radicalsfrom those mentioned in the following: hydroxyl radicals, C₃ - to C₆ -lower alkoxy radicals, C₁ - to C₆ - lower alkoxy-carbonyl radicals, C₁ -to C₆ - lower alkylthio radicals, halogen atoms, nitro groups, cyanoradicals, sulpho radicals, C₁ - to C₆ - lower alkylsulphonyl radicals,carboxylic acid groups, di-C₁ - to C₆ - lower alkylamino radicals,acetamido radicals and benzamido radicals. 2-Hydroxyethyl radicals,2-methoxyethyl radicals, ethoxy-carbonylmethyl radicals,methoxycarbonylmethyl radicals, 2-ethoxycarbonylethyl radicals, aceticacid and 3-propionic acid radicals, 2-dimethylaminoethyl radicals,3-dimethylaminopropyl radicals, 2-acetamidoethyl radicals and2-benzamidoethyl radicals are preferred here. The 2-hydroxyethylradical, the ethoxycarbonylmethyl radical, the methoxycarbonylmethylradical, the 2-di-methylaminoethyl radical and the 2-acetamidoethylradical are particularly preferred.

Examples of aryl radicals are the phenyl radical or the phenyl radicalsubstituted once, twice or three times by identical or differentradicals from those mentioned below: C₁ - to C₆ - lower alkyl radicals,C₁ - to C₆ - lower alkoxy radicals, C₁ - to C₆ - lower alkoxycarbonylradicals, C₁ - to C₆ - lower alkylthio radicals, hydroxyl radicals,halogen atoms, nitro groups, trifluoromethyl radicals, cyano radicals,sulpho radicals, alkylsulphonyl radicals, carboxylic acid groups,dialkylamino radicals, acetamido radicals, benzamido radicals, phenylradicals. Phenyl radicals, 2-fluorophenyl radicals, 3-fluorophenylradicals, 4-fluorophenyl radicals, 2-chlorophenyl radicals,3-chlorophenyl radicals, 4-chlorophenyl radicals, 2-bromophenylradicals, 3-bromophenyl radicals, 4-bromophenyl radicals, 2-iodophenylradicals, 3-iodophenyl radicals, 4-iodophenyl radicals, 2-methoxyphenylradicals, 3-methoxyphenyl radicals, 4-methoxyphenyl radicals,2-methoxycarbonylphenylradicals, 3-methoxycarbonylphenyl radicals,4-methoxycarbonylphenyl radicals, 2-methylphenyl radicals,3-methylphenyl radicals, 4-methylphenyl radicals,2-trifluoromethylphenyl radicals, 3-trifluoromethylphenyl radicals,4-trifluoromethylphenyl radicals, 2,4-dichlorophenyl radicals,3,4-dichlorophenyl radicals, 2,3-dichlorophenyl radicals,2,5-dichlorophenyl radicals, 2,4-dibromophenyl radicals,3,4-dibromophenyl radicals, 5 2,3-dibromophenyl radicals,2,5-dibromophenyl radicals, 2,4-dimethoxyphenyl radicals,3,4-dimethoxyphenyl radicals, 2,3-dimethoxyphenyl radicals,2,5-dimethoxyphenyl radicals, 2,4-dimethylphenyl radicals,3,4-dimethylphenyl radicals, 2,3-dimethylphenyl radicals,2,5-dimethylphenyl radicals, 2-ethylthiophenyl radicals,3-ethylthiophenyl radicals, 4-ethylthiophenyl radicals,2-dimethylaminophenyl radicals, 3-dimethylaminophenyl radicals,4-dimethylaminophenyl radicals, 2-acetamidophenyl radicals,3-acetamidophenyl radicals and 4-acetamidophenyl radicals are preferredhere. The phenyl radical, the 4-chlorophenyl radical, the2-methoxyphenyl radical, the 4-methoxyphenyl radical, the2-methoxycarbonylphenyl radical, the 4-methoxycarbonylphenyl radical,the 2-trifluoromethylphenyl radical, the 2,4-dichlorophenyl radical, the2,4-dimethoxyphenyl radical and the 4-acetamidophenyl radical areparticularly preferred. The phenyl radical, the 2-methoxyphenyl radical,the 4-methoxyphenyl radical, the 2-methoxycarbonylphenyl radical and the4-methoxycarbonylphenyl radical are very particularly preferred.

Aryl-C₁ - to C₆ - lower alkyl radicals are the C₁ - to C₆ - lower alkylradicals defined above, linked to an aryl radical which is as definedabove. Examples of aryl-lower alkyl radicals are benzyl radicals,phenethyl radicals, 4-fluorobenzyl radicals, 2-(4-fluorophenyl)-ethylradicals, 4-chlorobenzyl radicals, 2-(4-chlorophenyl)ethyl radicals,4-bromobenzyl radicals, 2-(4-bromophenyl)ethyl radicals, 4-iodobenzylradicals, 2-(4-iodophenyl)ethyl radicals, 2-hydroxybenzyl radicals,2-(2-hydroxyphenyl)ethyl radicals, 3-hydroxybenzyl radicals,2-(3-hydroxyphenyl)ethyl radicals, 4-hydroxybenzyl radicals,2-(4-hydroxyphenyl)ethyl radicals, 2-methoxybenzyl radicals,2-(2-methoxyphenyl)ethyl radicals, 4-methoxybenzyl radicals,2-(4-methoxyphenyl)ethyl radicals, 4-ethoxybenzyl radicals,2-(4-ethoxyphenyl)ethyl radicals, 4-tert-butoxybenzyl radicals,2-(4-tert-butoxyphenyl)ethyl radicals, 2,5-dimethoxybenzyl radicals,2,4-dimethoxybenzyl radicals, 4-methylbenzyl radicals,2-(4-methylphenyl)ethyl radicals, 4-nitrobenzyl radicals,2-(4-nitrophenyl)ethyl radicals, 2-dimethylaminobenzyl radicals,4-dimethylaminobenzyl radicals, 2-(4-dimethylaminophenyl)ethyl radicals,2-trifluoromethylbenzyl radicals, 3-trifluoromethylbenzyl radicals,4-trifluoromethylbenzyl radicals, 2-methoxycarbonylbenzyl radicals,4-methoxycarbonylphenyl radicals, 4-ethylmercaptobenzyl radicals or2-methoxy-5-methylbenzyl radicals.

Preferred aryl-C₁ - to C₆ - lower alkyl radicals are benzyl radicals,phenethyl radicals, 4-fluorobenzyl radicals, 4-chlorobenzyl radicals,4-bromobenzyl radicals, 4-iodobenzyl radicals, 2-methoxybenzyl radicals,4-methoxybenzyl radicals, 2-ethoxybenzyl radicals, 4-ethoxybenzylradicals, 2,5-dimethoxybenzyl radicals, 2,4-dimethoxybenzyl radicals,2-methylbenzyl radicals, 4-methylbenzyl radicals,2-methoxycarbonylbenzyl radicals, 4-methoxycarbonylbenzyl radicals,2-dimethylaminobenzyl radicals, 4-dimethylaminobenzyl radicals,2-trifluoromethylbenzyl radicals, 3-trifluoromethylbenzyl radicals,4-trifluoromethylbenzyl radicals, 2-acetamidobenzyl radicals and4-acetamidobenzyl radicals.

The benzyl radical, the 4-chlorobenzyl radical, the 2-methoxybenzylradical, the 2-ethoxybenzyl radical, the 2,4-dimethoxybenzyl radical,the 2-methoxycarbonylbenzyl radical, the 2-dimethylaminobenzyl radical,the 2-trifluoromethylbenzyl radical, the 2-acetamidophenyl radical, andthe 4-acetamidobenzyl radical are particularly preferred.

The benzyl radical, the 2-methoxybenzyl radical and the2-trifluoromethylbenzyl radical are very particularly preferred.

Examples of halogen atoms are fluorine, chlorine, bromine or iodineatoms.

Examples of a heterocyclic radical are radicals of saturated 5- or6-membered monocyclic heterocyclic rings which contain one, two or threeidentical or different heteroatoms such as nitrogen atoms, oxygen atomsor sulphur atoms.

Tetrahydrofuran-3-yl radicals, tetrahydropyran-4-yl radicals,N-methylpiperidin-3-yl radicals and N-methyl-piperidin-4-yl radicals arepreferred. The tetrahydrofuran-3-yl radical and theN-methylpiperidin-3-yl radical are particularly preferred.

Examples of radicals R⁴ in which R⁴ has the meaning of the generalformula (II) are methylcarbonyl radicals, propylcarbonyl radicals,methoxycarbonyl radicals, ethoxycarbonyl radicals, methylthio radicalsethylthio radicals, benzylthio radicals, methoxycarbonylmethylthioradicals, methoxy radicals, ethoxy radicals, benzyloxy radicals,methoxycarbonylmethoxy radicals. Ethylthio radicals, benzylthioradicals, methoxycarbonyl radicals, ethoxycarbonyl radicals andmethoxycarbonylmethylthio radicals are preferred.

If the compounds according to the invention are present in salt form,these are in this case salts with physiologically tolerable inorganic ororganic acids and bases. Examples of salts with physiologicallytolerable bases are ammonium, sodium, potassium, lithium, magnesium andcalcium salts, and also salts which ethanolamine, triethanolamine,morpholine or piperidine. Examples of salts with physiologicallytolerable acids are citrate-, tartrate-, acetate-, fumarate-,gluconate-, glutamate-, lactate-, malate-, maleate-, mesylate-,succinate-, carbonate-, hydrogencarbonate-, hydrogen-, sulphate-,phosphate-, hydrogenphosphate-, dihydrogen-, phosphate-, chloride-, andbromide-containing salts.

The synthesis of compounds of the general formula (I) is carried out inanalogy to processes known from the literature. The invention thereforealso relates to a process for the preparation of compounds of thegeneral formula (I), which is characterized in that a compound of thegeneral formula (III) ##STR3## in which X, Y, R², R³, m and n have theabovementioned meanings, is reacted with haloformic acid esters of thegeneral formula (IV) ##STR4## in which R¹ has the abovementioned meaningand Hal has the meaning fluorine or chlorine atoms, according to thefollowing reaction scheme: ##STR5##

Bases used can be both organic and inorganic bases, for example tertiaryamines, pyridine, sodium acetate, sodium and potassium hydroxide, sodiumand potassium carbonate, sodium and potassium hydrogen-carbonate, sodiumand calcium hydride and elemental sodium or potassium. Triethylamine,sodium carbonate and sodium hydride are particularly preferred here.(Compare the references: e.g. U. Petersen in Houben-Weyl, Methoden derOrganischen Chemie Methods of Organic Chemistry!, Volume E4,Kohlensaurederivate Carbonic acid derivatives!, p. 142 ff, Georg ThiemeVerlag, Stuttgart 1983 and references cited there).

Depending on the base used, methylene chloride, chloroform, toluene,ethyl acetate, acetone, tetrahydrofuran, dimethylformamide, pyridine oracetonitrile can be used as solvents. Methylene chloride, toluene,acetone and tetrahydrofuran are particularly preferred here.

Depending on the compound, the reactions are carried out with icecooling, at room temperature or at the boiling point of the respectivesolvent.

Alternatively, a compound of the general formula (III) is reacted withan appropriate carbonic acid diester of the general formula (V) ##STR6##in which R¹ has the abovementioned meaning and R⁹ is either identicalwith R¹ or forms a suitable leaving group R⁹ O⁻, such as e.g.electronegatively substituted phenoxy groups, (e.g. 4-nitro-, 2-nitro-,2,4-dinitro-, 2,3,5-trichloro-, or 4-acetylphenoxy) or suitablehydroxylamines (e.g. 1-hydroxypiperidine, N-hydroxysuccinimide orN-hydroxyphthalimide), according to the following reaction scheme:##STR7##

The reaction is carried out at about 100°-150° C. by fusion of the twocomponents or in a high-boiling solvent such as dimethylformamide ordimethyl sulphoxide.

In the case where in the compounds of the general formula (I) accordingto the invention the radicals R¹, R², R³, R⁴, R⁵ and R⁸ contain reactivegroups such as hydroxyl groups, mercapto groups, amino groups orcarboxylic acid radicals, these groups must be protected by protectivegroups in a suitable manner before the reaction. Methods for theprotection of these reactive groups are described in Theodora W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York1981.

The corresponding starting compounds having the general formula (III)##STR8## in which X, Y, R², R³, m and n have the abovementionedmeanings, are prepared following various methods known from theliterature:

isoquinolin-1(2 H)-one (X═CR⁴, Y═CR⁵): Beilstein 21, 100; Beilstein 21(3), 2245; G. S. Poindexter, J. Org. Chem. 47 (1982.) 3787 andreferences cited there; A. Couture, H. Cornet, P. Grandclaudon, J.Organomet. Chem. 440 (1992) 7 and references cited there.

1,2,3-Benzotriazin-4(3 H)-one (X═N, Y═N): Beilstein 26, 163; A. Weddige,H. Finger, J. Prakt. Chem. 35 (1887) 262; H. Finger, J. Prakt. Chem. 37(1888) 431; E. Zacharias, J. Prakt. Chem. 43 (1891) 446; D. Binder, Ch.R. Noe, F. Hillebrand, Arch. Pharm. 312 (1979) 845. 1(2 H)-Phthalazinone(X═N, Y═CR⁵): Beilstein 24, 142; S. Gabriel, A. Neumann, Chem. Ber. 26(1893) 523; v. Rothenburg, J. Prakt. Chem. 51 (1895) 147; C. Liebermann,A. Bistrzycki, Chem. Ber. 26 (1893) 535. Quinazolin-4(3 H)-one (X═CR⁴,Y═N): Beilstein 24, 143; R. Pech, R. Bohm, Pharmazie 44 (1989) 790; A.Ebenreth, R. Pech, R. Bohm, Pharmazie 47 (1992) 488; K. Hemender Reddy,A. Panduranga Reddy, V. Veeranagaiah, Indian J. Chem. 31B (1992) 163; C.G. Dave, P. R. Shah, A. B. Shah, Indian J. Chem. 31B (1992) 492.

Compounds of the general formula (IV) and also of the general formula(V) are obtained by reaction of the corresponding alcohols withphosgene, with trichloromethyl chloroformate or withbis(trichloromethyl) carbonate. Following methods known from theliterature (compare the reference: e.g. G. Heywang in Houben-Weyl,Methoden der Organischen Chemie Methods of Organic Chemistry!, VolumeE4, Kohlensaurederivate Carbonic acid 5 derivatives!, p. 9 ff, GeorgThieme Verlag, Stuttgart 1983 and references cited there; U. Petersen,ditto, p. 64 ff), the phosgene in this case can be allowed to actdirectly on lower alcohols, or both components are reacted with a basesuch as triethylamine or pyridine in an inert solvent such as methylenechloride or diethyl ether and, depending on the stoichiometry, compoundsof the general formula (IV) or (V) are obtained.

The compounds of the general formula (I) are useful pharmaceuticalactive compounds. As the applicant has surprisingly found, the compoundsaccording to the invention are distinguished by a good antithromboticactivity; they are free of undesired properties and thus very highlytolerable. These compounds are further potent inhibitors of enzymesbreaking down connective tissue, in particular granulocyte elastase.

Compounds having a similar structure to the compounds according to theinvention are known from the prior art (NL Patent 6702189; DE-OS1807685; Bull. Korean Chem. Soc. 11, 7 (1990); Reports Inst. Med. Dent.Eng. 8, 9 (1974); FR Patent 1460552). However, other actions of theseknown compounds are described than the compounds according to theinvention have.

Recently, the following relevant references have also been disclosed: CHPatent 540 266; FR Patent 1578785; JP Kokai 73 62,782; Chim. Ther. 2,202-212 (1967); GB Patent 1 365 806; JP Kokai 73 80,581; DE AS 2 451 417and JP A2 59-76069.

The actions of the compounds according to the invention make possibletheir use for the prevention and treatment of thromboembolic disordersor conditions and further for the prevention and treatment of diseaseswhich are associated with excessive breakdown of connective tissue, inparticular of the articular cartilage. Examples of thromboembolicdisorders in which the use of the substances according to the inventionis advantageous are deep and superficial venous thromboses and arterialthromboses such as cardiac infarct or ischaemic brain disorders.

Diseases which can be mentioned which are associated with excessivebreakdown of connective tissue and which can be treated with thecompounds according to the invention are especially arthritides andarthroses and also muscular dystrophy and pulmonary emphysema. A furthersyndrome which can be successfully treated with the elastase inhibitorsaccording to the invention is disseminated intravasal coagulation (DIC)which can occur in septic or traumatic shock or in burns.

In investigations on the antithrombotic action in the tail-bleeding timemodel on the rat in a modified test according to Diness (V. Diness etal., Thrombos. Haemostas. 55 (1986) 410-414) on groups of 10 rats,compounds according to the invention proved to be highly active on oraladministration. The compound from Example 14 at a dose of 200 mg/kg thusprolonged the bleeding time by 103%.

The inhibition of granulocyte elastase was determined in an enzymeinhibition test using elastase from human granulocytes. In this test thespecific substrate L-pyroglutaminyl-L-prolyl-L-valine-p-nitro-anilidewas used (J. A. Kramps et al., Scand. J. Lab. Invest. 43 (1983)427-432). The IC₅₀ values (concentrations for 50% inhibition) are shownin Table 1 for exemplary compounds according to the invention.

                  TABLE 1                                                         ______________________________________                                        Inhibition of granulocytic elastase                                           Compound from                                                                 example         IC.sub.50 (μM)                                             ______________________________________                                        1               0.20                                                          2               0.30                                                          4               8.30                                                          6               0.75                                                          13              4.00                                                          14              6.00                                                          15              5.40                                                          ______________________________________                                    

The invention therefore also relates to medicaments for the treatment ofhumans and animals, consisting of or containing one or more compounds ofthe general formula (I), if appropriate together with customaryexcipients and auxiliaries.

The compounds according to the invention can be administered in amultiplicity of pharmaceutical preparation forms and formulations, suchas, for example, tablets, coated tablets, capsules, pills, granules,liquid preparations to be administered orally, suppositories, solutions,suspensions and emulsions, pastes, ointments, gels, crees, lotions,patches, injection solutions, powders, sprays or aerosols, it beingpossible to use generally customary excipients and auxiliaries which arecompatible with the compounds according to the invention.

Besides the compounds of the general formula (1), the medicamentsaccording to the invention preferably contain non-toxic, inertpharmaceutically suitable excipients and auxiliaries. Non-toxic, inertpharmaceutically suitable excipients and auxiliaries are to beunderstood as meaning solid, semisolid or liquid diluents, fillers andformulation auxiliaries of any type.

Tablets, coated tablets, capsules, pills and granules may contain theactive compound or compounds together with the customary excipients.These include a) fillers and extenders, for example starches, lactose,cane sugar, glucose, mannitol, and silicic acid, b) binders, for examplecarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, c)humectants, for example glycerol, d) disintegrants, for exampleagaragar, calcium carbonate and sodium hydrogencarbonate, e) solutionretardants, for example paraffin, f) absorption accelerators, g) wettingagents, for example cetyl alcohol, glycerol monostearate, h) adsorbents,for example kaolin and bentonite and i) lubricants, for example talc,calcium and magnesium stearate and solid polyethylene glycols ormixtures of the substances mentioned under a) to i).

The tablets, coated tablets, capsules, pills and granules can beprovided with customary covering coatings which optionally containopacifying agents and are also thus composed such that they release theactive compound or compounds only or preferably in a certain part of theintestinal tract, if appropriate with a delay, it being possible to use,for example, polymeric substances and waxes as embedding materials. Theactive compound or compounds can optionally also be present inmicroencapsulated form with one or more of the excipients indicatedabove.

Besides the active compound or compounds, suppositories can contain thecustomary water-soluble or water-insoluble excipients, for examplepolyethylene glycols, fats, for example cocoa fat, and higher esters(for example C₁₄ -alcohol with C₁₆ -fatty acid or mixtures of thesesubstances).

In addition to the active compound or compounds, as an oily base creamsprimarily contain fatty alcohols, for example lauryl, cetyl, or stearylalcohol, fatty acids, for example palmitic or stearic acid, liquid tosolid waxes, for example isopropyl myristate, wool wax or beeswax and/orhydrocarbons, for example petroleum jelly (petroleum) or liquidparaffin. Emulsifiers used are preferably those having mainlyhydrophilic properties, for example non-ionic emulsifiers such as fattyacid esters of polyalcohols, ethylene oxide adducts of polyalcohols suchas polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acidesters (Tweens) or ionic emulsifiers such as alkali metal salts of fattyalcohol sulphates, for example sodium lauryl sulphate, sodium cetylsulphate or sodium stearyl sulphate. Agents can be added to the waterphase which prevent the drying out of the cream, for examplepolyalcohols such as glycerol, sorbitol, propylene glycol and/orpolyethylene glycols.

Besides the active compound or compounds, possible excipients forointments are primarily hydrocarbons, for example petroleum jelly orliquid paraffin, which for improving the water-binding power preferablycontain suitable fatty alcohols or esters thereof, for example cetylalcohol or wool wax. Emulsifiers are appropriate lipophilic substancessuch as sorbitan fatty acid esters. Humectants such as, for example,glycerol or propylene glycol can be added to the water phase.

Besides the active compound or compounds sprays and powders can containthe customary excipients, for example lactose, talc, silicic acid,alumina, calcium silicate and polyamide powder or mixtures of thesesubstances. Sprays can additionally contain the customary propellants.

Besides the-active compound or compounds, solutions and emulsions cancontain the customary excipients such as solvents, solubilizers andemulsifiers, for example water, ethanol, isopropanol, ethyl carbonate,benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,oils, in particular cottonseed oil, groundnut oil, maize oil, castoroil, cashew nut oil and sesame oil, glycerol, glycerol formal,polyethylene glycols and fatty acid esters of sorbitan or mixtures ofthese substances.

Besides the active compound or compounds, suspensions can contain thecustomary excipients such as liquid diluents, for example ethanol,propylene glycol, suspending agents, for example ethoxylated isostearylalcohol's, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminium metahydroxide, bentonite,agar-agar or tragacanth or mixtures of these substances.

The said formulation forms can also contain colourants, preservativesand also smell- and taste-improving additives, for example peppermintoil and eucalyptus oil and sweeteners, for example saccharin.

The compounds according to the invention are preferably contained in theabovementioned pharmaceutical preparations in a concentration of about0.1 to 99.5, particularly preferably of about 0.5 to 95, % by weight ofthe total mixture.

Apart from the active compounds according to the invention, theabovementioned pharmaceutical preparations can also contain furtherpharmaceutical active compounds.

The abovementioned pharmaceutical preparations are prepared in acustomary manner by known methods, for example by mixing the activecompounds with the excipients.

The present active compounds or pharmaceutical preparations, whichcontain one or more active compounds, can be employed in human andveterinary medicine for the prevention, amelioration and/or cure ofthromboembolic diseases or conditions, or of diseases in which anexcessive breakdown of connective tissue is of importance.

In general, it has proven advantageous in human medicine to use theactive compound or compounds according to the invention in total dosesof about 1 to about 2000 mg, preferably 5 to 1000 mg, daily, inparticular one to four dose units per day being administered to achievethe desired results.

However, it may be necessary to depart from the dosages mentioned,mainly depending on the species and the body weight of the subject to betreated, the nature and the severity of the disorder, the manner ofpreparation and administration of the medicament and the period orinterval within which administration takes place. Thus, in some cases itmay be adequate to manage with less than the abovementioned amount ofactive compound, while in other cases the abovementioned amount ofactive compound must be exceeded.

The following examples illustrate the invention in greater detailwithout restricting its scope.

EXAMPLES

Example 1

Phenyl 1(2 H)-phthalazinone-N-carboxylate

4.38 g (30 mmol) of 1(2 H)-phthalazinone and 4.16 ml (30 mmol) oftriethylamine are dissolved in 150 ml of dichloromethane and a solutionof 3.33 ml (35 mmol) of ethyl chloroformate is added dropwise at 0° C.in 50 ml of dichloromethane. After stirring at room temperature for 12hours, the solution obtained is washed three times with 50 ml of waterin each case and dried over sodium sulphate, and the solvent is removed.The residue crystallizes completely after some time. Alternatively, itis stirred with diisopropyl ether until complete crystallization.Subsequent recrystallization from ethanol yields the title compound in76% yield.

Colourless crystals; m.p.: 74° C.

¹ H-NMR (CDCl₃): δ(ppm)=7.28-8.54 (m; Ar--H).

IR (Nujol; cm⁻¹): 3045, 3025, 1784, 1775(sh), 1693, 1670(sh), 1600,1486, 1321, 1297, 1268, 1241, 1208, 1192, 1168, 1154, 761, 748, 719,688, 682.

Examples 2-14:

In analogy to the above procedure, the following title compounds areobtained by reaction of the respective starting compounds((Isoquinolin-1(2H)-one, 1,2,3-benzotriazin-4(3 H)-one, 1(2H)-phthalazinone/-derivatives or quinazolin-4(3 H)-one/derivatives) withthe appropriate chloroformic acid esters. Crystallization orpurification is carried out by stirring in a suitable solvent such as.petroleum ether, diisopropyl ether or diethyl ether, byrecrystallization in solvents such as cyclohexane, toluene, xylene,diisopropyl ether, tert-butyl methyl ether, ethanol or isopropanol or bycolumn chromatography:

                                                                                     - Ex. No. Starting Compound Haloformic acid ester Title compound M.p.         (°C.)                                                                    2                                                                              ##STR9##                                                                       ##STR10##                                                                      ##STR11##                                                                      oil                                                                           3                                                                               ##STR12##                                                                      ##STR13##                                                                      ##STR14##                                                                      76                                                                            4                                                                               ##STR15##                                                                      ##STR16##                                                                      ##STR17##                                                                      143                                                                              5                                                                            ##STR18##                                                                      ##STR19##                                                                      ##STR20##                                                                      112                                                                              6                                                                            ##STR21##                                                                      ##STR22##                                                                      ##STR23##                                                                      192                                                                              7                                                                            ##STR24##                                                                      ##STR25##                                                                      ##STR26##                                                                      137                                                                              8                                                                            ##STR27##                                                                      ##STR28##                                                                      ##STR29##                                                                      118                                                                              9                                                                            ##STR30##                                                                      ##STR31##                                                                      ##STR32##                                                                      72                                                                            10                                                                              ##STR33##                                                                      ##STR34##                                                                      ##STR35##                                                                      58                                                                            11                                                                              ##STR36##                                                                      ##STR37##                                                                      ##STR38##                                                                      oil                                                                           12                                                                              ##STR39##                                                                      ##STR40##                                                                      ##STR41##                                                                      92                                                                            13                                                                              ##STR42##                                                                      ##STR43##                                                                      ##STR44##                                                                      72                                                                            14                                                                              ##STR45##                                                                      ##STR46##                                                                      ##STR47##                                                                      35                                                                       

Example 15:

Ethyl 5-ethoxycarbonyloxyisoquinolin-1(2 H)-one-N-carboxylate

4.83 g (30 mmol) of 1,5-isoquinolinediol and 8.32 ml (60 mmol) oftriethylamine are dissolved in 150 ml of dichloromethane and a solutionof 6.67 ml (70 mmol) of ethyl chloroformate is added dropwise at 0° C.in 50 ml of dichloromethane. After stirring at room temperature for 12hours the solution obtained is washed twice with 50 ml of 2 N sodiumhydroxide solution in each case and three times with 50 ml of water ineach case and dried over sodium sulphate, and the solvent is removed.The residue crystallizes after some time and is stirred with petroleumether until complete crystallization. The title compound is obtained in82% yield.

Colourless crystals; m.p.: 71° C.

¹ H-NMR (CDCl₃): δ(ppm)=1.40 (t, ³ J=7 Hz; 3 H, --CH₂ --CH₃), 1.46 (t, ³J=7 Hz; --CH₂ --CH₃), 4.35 (q, ³ J=7 Hz; 2H, --CH₂ --CH₃), 4.53 (q, ³J=7 Hz; 2H, --CH₂ --CH₃), 6.56 (d, ³ J=8 Hz; 1 H, R⁵ ═H), 7.43-7.70 (m;4 H, C--H_(aromat)), 8.31 (d, ³ J=8 Hz; 1 H, R⁴ =H)

IR (Nujol; cm⁻¹): 3135, 3115, 1754, 1734, 1694, 1640, 1609, 1562, 1310,1279, 1259, 1233, 1177, 1148, 1136, 1114, 1086, 1057, 1000, 956, 924,912, 887, 860, 850 820, 769, 756, 739, 720, 700, 689, 637.

Example 16:

N'-Methylpiperidin-3-yl isoquinolin-1(2 H)-one-N-carboxylate

A solution of 4.04 ml (35 mmol) of 3-hydroxy-N-methylpiperidine and 4.85ml (35 mmol) of triethylamine in 50 ml of dichloromethane is addeddropwise at 0° C. to a solution of 2.11 ml (17.5 mmol) oftrichloromethyl chloroformate ("diphosgene") in 150 ml ofdichloromethane and the mixture is then stirred at room temperature for3 hours. 4.35 g (30 mmol) of solid isoquinolin-1(2 H)-one("isocarbostyril") are added to the resulting colourless suspension withice cooling, a solution of 4.15 ml (30 mmol) of triethylamine in 50 mlof dichloromethane is added dropwise and the mixture is stirredovernight at room temperature. The solution, which is now clear, iswashed once with 50 ml of half-saturated sodium hydrogen carbonatesolution and three times with 50 ml of water in each case, dried oversodium sulphate and brought to dryness. The residue is stirred severaltimes with petroleum ether, the combined filtrates are completely freedfrom the solvent and the residue is then left to crystallize. The titlecompound is obtained in 90% yield. Colourless crystals; m.p.: 76° C.

¹ H-NMR (CDCl₃): δ(ppm)=1.52-2.98 (m; 8 H, C--H_(aliphat)), 2.30 (s; 3H, N--CH₃), 5.12 (m; 1 H, --O--CH), 6.41 (d, ³ J=8.4 Hz; 1 H, R⁵ ═H)7.32-7.77 (m; 4 H, C--H_(aromat)), 8.40 (d, ³ J=8.4 Hz; 1 H, R⁴ ═H).

IR (Nujol; cm⁻¹): 3115, 3058, 2778, 1774, 1736, 1684, 1632, 1602, 1461,1404, 1310, 1282, 1258, 1249, 1224, 1199, 1169, 1132, 1096, 1083, 1060,1022, 997, 961, 882, 861, 782, 768, 683.

Examples 17-18

As described in Example 16, the following title compounds are obtainedby reaction of the respective starting compounds (1,2,3-benzotriazin-4(3H)-one, 1(2 H)-phthalazinone) with the appropriate alcohols and withtrichloromethyl chloroformate ("diphosgene"). Crystallization orpurification is carried out by stirring in a suitable Solvent such aspetroleum ether, diisopropyl ether or diethyl ether, byrecrystallization in solvents such as cyclohexane, toluene, xylene,diisopropyl ether, tert-butyl methyl ether, ethanol or isopropanol or bycolumn chromatography:

    __________________________________________________________________________    Ex.                                                                              Starting    Haloformic     Title                  M.p.                     No.                                                                              Compound    acid ester     compound               (°C.)             __________________________________________________________________________    17                                                                                ##STR48##                                                                                 ##STR49##                                                                                    ##STR50##             112                      18                                                                                ##STR51##                                                                                 ##STR52##                                                                                    ##STR53##             118                      __________________________________________________________________________

Example 19:

N'-Methylpiperidin-3-yl isoquinolin-1(2 H)-one-N-carboxylatehydrochloride

Hydrogen chloride is introduced at 0° C. into a solution of 5.72 g (20mmol) of N'-methylpiperidin-3-yl isoquinolin-1(2 H)-one-N-carboxylate in200 ml of diisopropyl ether until it is saturated, the suspensionobtained is stirred at room temperature for a further 2 h, and the.precipitate is then filtered off with suction under nitrogen, washedwith diisopropyl ether and with petroleum ether and dried overphosphorus pentoxide in vacuo. The very hygroscopic title compound isobtained in quantitative yield.

Colourless powder; deliquesces in air

¹ H-NMR (d6-DMSO): δ(ppm)=1.51-3.93 (m; 8 H, C--H_(aliphat)), 2.83 (s; 3H, N--CH₃), 5.05 (m; 1 H, --O--CH), 6.63 (d, ³ J=8 Hz; 1 H, R⁵ ═H)7.48-7.88 (m; 4 H, C--H_(aromat)), 8.25 (d, ³ J=8 Hz; 1 H, R⁴ ═H).

IR (KBr; cm⁻¹): 3425, 3065, 2950, 2673, 2555, 2512, 1772, 1672, 1631,1602, 1461, 1406, 1329, 1292, 1256, 1230, 1197, 1148, 1130, 1102, 1091,1042, 1007, 980, 954, 884, 788, 769, 685.

Example 20:

2'-Hydroxyethyl 1(2 H)-phthalazinone-N-carboxylate

5.85 g (40 mmol) of 1(2 H)-phthalazinone and 3.96 g (45 mmol) ofethylene carbonate are dissolved together in 50 ml of dimethylformamideand heated at about 150° to 160° C., (bath temp.) for 10 h. Aftercooling, the mixture is treated with 300 ml of water and extracted threetimes by shaking with 100 ml of ethyl acetate in each case, the combinedorganic phases are washed three times with 50 ml of water each time anddried over sodium sulphate, and the solvent is completely removed. Thetitle compound crystallizes to 16% from xylene.

Slightly yellow crystals: m.p.: 107° C.

¹ H-NMR (CDCl₃): δ=3.45 (t, ³ J=4.3 Hz; 1 H, --CH₂ --OH), 4.09(dt, ³J_(d) =4.3 Hz, ³ HJ_(t) =4.8 Hz; 2 H, --CH₂ --CH₂ --OH), 4.45 (t, ³J_(t) =4.8 Hz; 2 H, --O--CH₂ --CH₂ --), 7.60-7.92 (m; 3 H,C--H_(aromat)), 8.17 (s; 1 H, R⁵ ═H), 8.33-8.45 (m; 1 H, C--H_(aromat)).

IR (Nujol; cm⁻¹): 3375, 1632, 1580, 1284, 1250, 1148, 1071, 1049, 972,918, 864, 762, 738, 684.

Example 21:

2'-Hydroxyethyl 1,2,3-benzotriazin-4(3 H)-one-N-carboxylate

11.77 g (80 mmol) of 1,2,3-benzotriazin-4(3 H)-one and 7.93 g (90 mmol)of ethylene carbonate are dissolved together in 50 ml ofdimethylformamide and the mixture is heated for 10 hours at about 150 to160° C. (bath temp.); the solvent is then removed in vacuo and theresidue is stirred several times with petroleum ether and finally withdiisopropyl ether until crystallization is complete.

The title compound crystallizes to 53% from xylene.

Slightly orange-coloured crystals; m.p.: 110° C.

Example 22:

Recipe for the production of tablets: 1000 tablets are prepared from thecompounds below in the manner described below. One tablet then contains100 mg of phenyl 1(2 H)-phthalazinone-N-carboxylate as active compound.

    ______________________________________                                        1.     Phenyl 1(2H)-phthalazinone-N-carboxylate                                                              100    g                                       2.     Lactose                 263    g                                       3.     Microcrystalline cellulose                                                                            120    g                                       4.     Maize starch            60     g                                       5.     Magnesium stearate      7      g                                       ______________________________________                                    

1) and 2) are mixed, 3) and 4) are intermixed, 5) is added finally andmixed and the mixture is pressed directly.

Example 23:

Recipe for production of a cream:

The following recipe yields a 5% phenyl 1(2H)-phthalazinone-N-carboxylate cream (substance data in % by weight):

    ______________________________________                                        Phenyl 1(2H)-phthalazinone-N-carboxylate                                                             5.00                                                   Emulsifier (mixture of sodium glyceryl                                                               10.00                                                  monostearate, sodium stearyl sulphate                                         and sodium cetyl sulphate)                                                    Medium-chain triglycdrides                                                                           6.25                                                   Myristyl alcohol       5.00                                                   POE-12-cetylstearyl alcohol                                                                          3.00                                                   Preservative           q.s.                                                   Water                  ad 100.00                                              ______________________________________                                    

We claim:
 1. Compounds of the formula (I) ##STR54## a) X denotes thegroup CR⁴ and Y denotes the group CR⁵, whereR¹ represents a C₁ - to C₆ -lower alkyl group, a substituted C₁ - to C₆ - lower alkyl group, anaryl-C₁ - to C₆ - lower alkyl group, an aryl group or a heterocyclicgroup, R² and R³ independently of one another represent the followinggroups: hydrogen atoms, C₁ - to C₆ - lower alkyl groups, C₁ - to C₆ -lower alkoxy groups, C₁ - to C₆ - lower alkylthio groups, halogen atoms,nitro groups, hydroxyl groups, trifluoromethyl groups, cyano groups,sulpho groups, C₁ - to C₆ - lower alkoxycarbonyl groups, carboxylic acidgroups, C₁ - to C₆ - lower alkoxycarbonyl groups, C₁ - to C₆ - loweralkoxycarbonyloxy groups, acetamido groups, benzamido groups or thegroup --N(R⁶)R⁷, R⁴ and R⁵ independently of one another represent ahydrogen atom, a C₁ - to C₆ - lower alkyl groups, a substituted C₁ - toC₆ - lower alkyl group, an aryl-C₁ - to C₆ - lower alkyl group or anaryl group, m and n independently of one another are equal to 0, 1, 2,3, or 4, and R⁶ and R⁷ independently of one another represent a hydrogenatom or a C₁ - to C₆ - lower alkyl group, or in whichb) X and Y denote enitrogen atom, where R¹ represents a methyl group, a c₃ - to c₆ - loweralkyl group, a substituted C₁ - to C₆ - lower alkyl group, an aryl-C₁ -to C₆ - lower alkyl group, an aryl group or a heterocyclic group, R² andR³ independently of one another represent the following groups: hydrogenatoms, C₁ - to C₆ - lower alkyl groups, C₁ - to C₆ - lower alkoxygroups, C₁ - to C₆ - lower alkylthio groups, halogen atoms, nitrogroups, hydroxyl groups, trifluoromethyl groups, cyano groups, sulphogroups, C₁ - to C₆ - lower alkylsulphonyl groups, carboxylic acidgroups, C₁ - to C₆ - lower alkoxycarbonyl groups, C₁ - to C₆ - loweralkoxycarbonyloxy groups, acetamido groups, benzamido groups or thegroup --N(R⁶)RT⁷, and m and n, R⁶ and R⁷ have the meanings mentionedunder a), with the proviso that is R¹ denotes a methyl group, anunsubstituted C₃ - to C₆ - lower alkyl group, a phenyl group or a benzylgroup, at least one group R² or R³ is different from a hydrogen atom ora halogen atom, or in which c) X denotes a nitrogen atom and Y denotesthe group CR⁵, where R¹ represents a substituted C₁ - to C₆ - loweralkyl group, an aryl-C₁ - to C₆ - lower alkyl group, an aryl group or aheterocyclic group, R² and R³ independently of one another have themeanings mentioned under a), R⁵ represents a hydrogen atom or a C₁ - toC₆ - lower alkyl group, and m and n, R⁶ and R⁷ have the meaningsmentioned under a), or in which d) X denotes a nitrogen atom and Ydenotes the group CR⁵, where R¹ represents a C₁ - to C₆ - lower alkylgroup, a substituted C₁ - to C₆ - lower alkyl group, an aryl-C₁ - toC₆ - lower alkyl group, an aryl group or a heterocyclic group, R² and R³independently of one another have the meanings mentioned under a), R⁵represents a substituted C₁ - to C₆ - lower alkyl group, an aryl-C₁ - toC₆ - lower alkyl group or an aryl group, and m and n, R⁶ and R⁷ have themeanings mentioned under a), or in which e) Y denotes a nitrogen atomand X denotes the group CR⁴, where R¹ represents a C₁ - to C₆ - loweralkyl group, a substituted C₁ - to C₆ - lower alkyl group, an aryl-C₁ -to C₆ - lower alkyl, group, an aryl group or a heterocyclic group, R²and R³ independently of one another have the meanings mentioned undera), R⁴ represents a substituted C₁ - to C₆ - lower alkyl group otherthan an ethyl ester or a group of the formula (II)

    --Z--R.sup.8                                               (II)

where Z represents a carbonyl or carboxyl group, a sulfur atom or anoxygen atom and R⁸ represents a C₁ - to C₆ - lower alkyl group, asubstituted C₁ - to C₆ - lower alkyl group, an aryl-C₁ - to C₆ - loweralkyl group or an aryl group, and m and n, R⁶ and R⁷ have the meaningsmentioned under a), or in which f) Y denotes a nitrogen atom and Xdenotes the group CR⁴, where R¹ represents a substituted C₁ - to C₆ -lower alkyl group, an aryl group or a heterocyclic group, R² and R³independently of one another have the meanings mentioned under a), R⁴represents a hydrogen atom, a C₁ - to C₆ - lower alkyl group, asubstituted C₁ - to C₆ - lower alkyl group, an aryl-C₁ - to C₆ - loweralkyl group or an aryl group, and m and n, R⁶ and R⁷ have the meaningsmentioned under a), with the proviso that if R², R³ and R⁴ denotehydrogen atoms, R¹ is different from an unsubstituted phenyl group, andtheir salts with physiologically acceptable acids and bases. 2.Compounds of the formula (I) according to claim 1, wherein X denotes thegroup CR⁶ and Y denotes the group CR⁵, and R¹, R², R³, R⁴, R⁵, m and nhave the meanings set forth in claim 1a.
 3. Compounds of the formula (I)according to claim 1, wherein X and Y denote a nitrogen atom, and R¹,R², R³, m and n have the meanings set forth in claim 1b.
 4. Compounds ofthe formula (I) according to claim 1, wherein X denotes a nitrogen atomand Y denotes the group CR⁵, and R¹, R², R³, R⁵, m and n have themeanings set forth in claim 1c.
 5. Compounds of the formula (I)according to claim 1, wherein X denotes a nitrogen atom and Y denotesthe group CR⁵, and R¹, R², R³, R⁵, m and n have the meanings set forthin claim 1d.
 6. Compounds of the formula (I) according to claim 1,wherein Y denotes a nitrogen atom and X denotes the group CR⁴, and R¹,R², R³, R⁴, R⁸, m and n have the meanings set forth in claim 1e. 7.Compounds according to claim 2, wherein R⁴ and R⁵ denote a hydrogenatom.
 8. Compounds according to claim 3, wherein R² and R³ denotehydrogen atoms.
 9. Compounds of the formula (I) ##STR55## wherein X andY denote a nitrogen atom, R¹ denotes a substituted C₁ - to C₆ - loweralkyl group, an aryl C₁ - to C₆ - lower alkyl group, an aryl group or aheterocyclic group,R² and R³ independently of one another represent thefollowing groups: hydrogen atoms, C₁ - to C₆ - lower alkyl groups, C₁ -to C₆ - lower alkoxy groups, C₁ - to C₆ - lower alkylthio groups,halogen atoms, nitro groups, hydroxyl groups, trifluoromethyl groups,cyano groups, sulpho groups, C₁ - to C₆ - lower alkylsulphonyl groups,carboxylic acid groups, C₁ - to C₆ - lower alkoxycarbonyl groups,acetamido groups, benzamido groups, benzamido groups or the group--N(R⁶)R⁷,R⁴ and R⁵ independently of one another represent a hydrogenatom, a C₁ - to C₆ - lower alkyl group, a substituted C₁ - to C₆ - loweralkyl group, an aryl-C₁ - to C₆ - lower alkyl group, or an aryl group, mand n independently of one another are equal to 0, 1, 2, 3, or 4, and R⁶and R⁷ independently of one another represent a hydrogen atom or a C₁ -to C₆ - lower alkyl group.
 10. Compounds according to claim 4, whereinR¹ denotes a substituted C₁ - to C₆ - lower alkyl group.
 11. Compoundsaccording to claim 4, wherein R¹ denotes an aryl group.
 12. Compoundsaccording to claim 6, wherein R⁴ had the meaning of formula (II) and ZXrepresents a sulfur atom or carboxyl group.
 13. Compounds according toclaim 6, wherein R¹ denotes an aryl group or a heterocyclic group. 14.Process for the preparation of compounds of formula (I), comprisingreacting a compound of the formula (III) ##STR56## in which X, Y, R²,R³, , and n have the meanings as in claim 1, in the presence of a basewith the appropriate haloformic acid esters of the formula ##STR57## inwhich R¹ has the meaning as in claim 1, and Hal has the meaning fluorineor chlorine atoms.
 15. A pharmaceutical composition comprising one ormore compounds set forth in claim 1 and a pharmaceutically acceptablecarrier therefor.